Pharmacokinetics-Pharmacodynamics of Tazobactam in Combination with Piperacillin in an In Vitro Infection Model

We have previously demonstrated the pharmacokinetic-pharmacodynamic (PK-PD) index best associated with the efficacy of tazobactam when used in combination with ceftolozane to be the percentage of the dosing interval during which tazobactam concentrations remained above a threshold value (% time>threshold). Using an in vitro infection model and the same isogenic CTX-M-15-producing Escherichia coli triplet set genetically engineered to transcribe different levels of bla(CTX-M-15), herein we describe dose fractionation studies designed to evaluate the PK-PD index associated with tazobactam efficacy, when given in combination with piperacillin, and the impact of the presence of a different beta-lactam agent, or different bla(CTX-M-15) transcription levels, on the magnitude of the tazobactam PK-PD index necessary for efficacy. The recombinant strains demonstrated piperacillin MIC values of 128,>256, and >256 mu g/ml for the low-, moderate-, and high-level CTX-M-15-producing E. coli strains, respectively. The MIC value for piperacillin in the presence of 4 mu g/ml of tazobactam was 2 mu g/ml for all three strains. The PK-PD index associated with tazobactam efficacy was confirmed to be % time>threshold, regardless of beta-lactamase transcription (r(2) = 0.839). The tazobactam concentration thresholds, however, changed with the CTX-M-15 transcription level and were 0.25, 0.5, and 2 mu g/ml for the low-, moderate-, and high-level CTX-M-15-producing strains, respectively (r(2) = 0.921, 0.773, and 0.875, respectively). The % time>threshold values for tazobactam necessary for net bacterial stasis and a 1- and 2-log(10)-unit CFU/ml decrease from baseline at 24 h were 44.9, 62.9, and 84.9%, respectively. In addition to verifying our previous study results, these results also demonstrated that the magnitude of bacterial-cell killing associated with a beta-lactam-beta-lactamase inhibitor combination is dependent on the amount of beta-lactamase produced. These data provide important information for the development of beta-lactam-beta-lactamase inhibitor combination agents.